AAV1-CMV-NULL

Fibroblast growth factor 21 (FGF21) is considered a promising therapeutic agent for type 2 diabetes (T2D) and obesity. However, native FGF21 has poor pharmacokinetic properties, making gene therapy an attractive strategy to achieve sustained circulating levels of this protein. Here, adeno-associated viral vectors (AAV) are used to genetically modify liver, adipose tissue, or skeletal muscle to secrete FGF21. Treatment of chronically high-fat diet-fed animals or ob/ob mice resulted in significant reductions in body weight, adipose tissue hypertrophy and inflammation, hepatic steatosis, inflammation and fibrosis, and insulin resistance, lasting over 1 year. This therapeutic effect was achieved without side effects despite persistent elevations in serum FGF21. Furthermore, overproduction of FGF21 protects against weight gain and aging-related insulin resistance in healthy animals fed a standard diet. These studies highlight the potential of FGF21 gene therapy to treat obesity, insulin resistance, and T2D.

Circulating levels of FGF21 were measured 40 weeks after injection of AAV1-CMV-null or AAV1-CMV-FGF21 vector into the skeletal muscle of healthy animals fed regular chow and showed a significant increase in circulating FGF21 (Figure 1A). This is consistent with the high level expression of vector-derived FGF21 in the three injected muscles (Figure 1B). This combination of vector serotype, promoter, and route of administration did not result in transgene expression in the liver (Figure 1B). At the end of the approximately 10-month follow-up period, mice injected intramuscularly with AAV1-CMV-FGF21 maintained their body weight at the start of the study by approximately 38% more than AAV1-CMV-null controls, and as the animals aged, they The body weight increased steadily (Figure 1C). While muscle weight was barely affected by FGF21 gene transfer, the weight of white and brown depots, as well as liver, was significantly reduced. In addition, liver total triglyceride content was significantly reduced in mice treated with AAV1-CMV-FGF21. At the end of the study, FGF21-treated mice showed significant improvements in insulin sensitivity. In conclusion, this study demonstrates that in healthy humans, long-term use of AAV vectors that result in therapeutically relevant levels of circulating FGF21 is safe and may be used to counteract aging-related weight gain and insulin resistance.

Figure 1. Gene transfer of FGF21 to the skeletal muscle of healthy animals. (Jimenez V, et al., 2018)